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An MD&DI June 1999 Column

FDA's budgetary problems are garnering little sympathy with device manufacturers, who remain unmoved by renewed calls for user fees.

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With new-drug-review user fees such a demonstrable success, it's no wonder that the Clinton administration comes back to Congress year after year with budget proposals incorporating user fees for medical devices. This year, FDA's dire fiscal condition has made the agency a more enthusiastic supporter of this heretofore futile administration ploy. Given the die-hard opposition of industry, however, the results are likely to be a rerun of the past.

The reason is simple enough. Drug user fees had that industry's support, but device user fees have received a cold shoulder from the medical industry. The drug model is therefore no template for medical device approvals, even though the administration, and now FDA's Center for Devices and Radiological Health (CDRH) itself, see user fees as the only way out of a deteriorating situation.

Outgoing CDRH director Bruce Burlington, in an unprecedented series of "SOS" one-on-one calls to selected CEOs, has pleaded for an industry change of heart. It's not known how much encouragement he received, although some major companies are believed to be willing to pay user fees in exchange for faster approvals.

Burlington's call-around preceded a similarly urgent pitch by Dan Mendelson of the Office of Management and Budget (OMB) to the assembled board of the Health Industry Manufacturers Association (HIMA) at its annual meeting on March 14, urging support for President Clinton's budget and its $7 million of device user fees. The HIMA board gave Mendelson a polite hearing but later voted to make no decision. Officially, HIMA remained willing to keep listening.

Four days later, however, HIMA testified on Capitol Hill that FDA would be well advised to look elsewhere for fiscal relief. Suggested alternatives included using outside resources through mutual recognition agreements (MRAs), under which other parties do some of FDA's work for free. HIMA told Congress that more MRAs like the U.S.—European Union agreement on third-party reviews could ultimately save FDA money and resources, but that it will take a larger short-term commitment than the agency has yet made for the fruits of these pacts to be realized.

More MRAs are the building blocks "to a new global system that will reduce unnecessary, time-consuming, and costly regulatory redundancies," HIMA said. "Aggressive and full participation by FDA in discussions with nations on a common-sense approach to regulatory requirements worldwide will hasten the day when international harmonization becomes a reality."

HIMA also suggested that FDA should be encouraged to accept foreign inspection reports from internationally recognized organizations. Regarding FDA's biennial inspection requirement, statutory flexibility should be exercised for certain manufacturers through a risk-based inspection approach, the group indicated.

Another promising area that should get additional funding is FDA's sentinel surveillance system, HIMA said. This program is designed to replace adverse-event reporting by hospitals and other users and has the ability to capture more meaningful information than the current medical device reporting by manufacturers, said HIMA. The association recommended that FDA establish a working group comprising industry, users, and agency experts to further develop the system to meet the needs of all parties.

HIMA also questioned the administration's allocation request of $15 million for enhancing FDA's adverse-event reporting system. "We know little about the system and simply urge Congress to ensure that there is a real need for this system and that its benefits will justify its costs," HIMA said. "We believe that the system could benefit from an open airing of the agency's plans early in the design stages."

While HIMA maintained a diplomatic stance of listening while pointing elsewhere, its more aggressive counterpart for smaller firms, the Medical Device Manufacturers Association (MDMA), came out with a blunt-instrument approach. It told OMB that the administration's $7 million user-fee request amounted to an unjust tax on companies that simply could not afford to pay.

Most of the more than 8000 medical device firms are very small, MDMA said, and are not supported by venture capital even though they are responsible for most breakthroughs in medical technology. MDMA told OMB that the 50 largest medical device manufacturers in the United States only submitted 10 of the 46 premarket approval (PMA) applications approved last year.

FDA, the group suggested, should focus on its "voluntary user-fee program"—the third-party review program for low- to moderate-risk devices mandated by the FDA Modernization Act of 1997 (FDAMA). "By promoting this program to manufacturers and by expanding the list of eligible devices, FDA could use third-party review to obviate the need for a significant infusion of new resources."

CDRH has shown that it can cut by half the amount of time FDA investigators require to perform a comprehensive medical device inspection by following the center's new quality system inspection technique (QSIT). FDA tested the QSIT program late last year by conducting 40 device inspections in the Minneapolis, Denver, and Los Angeles districts.

So far, early evaluations by investigators and questionnaires returned by inspected companies paint a positive picture and leave the center with few reasons not to implement the technique as the standard and future model for device inspections. The pilot inspections proved to be better focused and shorter: a preliminary review showed the average QSIT inspection lasting only 43 hours compared with the average 80 hours that investigators normally take to conduct a comprehensive inspection.

Under the QSIT program, investigators follow a handbook that provides a road map of how to conduct a quality system inspection. Based on a review of the warning letters generated by the pilot program, agency officials are pleased that most findings were significant and in line with the QSIT handbook. This means that the inspections have been very focused, according to a CDRH official. The inspections also are more closely harmonized with European inspections, the official added.

In QSIT inspections, investigators evaluate four subsystems of the quality system regulation: management controls, design controls, corrective and preventive actions, and production and process controls. The program is designed for only one investigator, instead of a team approach, which helps the agency free up resources to conduct more inspections.

FDA officials are adding three new inspection programs to the evaluation of the correction and preventive actions subsystem. These include medical device reporting, device tracking, and corrections and removals. A complete QSIT evaluation of these three programs is expected to add approximately 4 hours to the average inspection.

A new, risk-based model developed by CDRH could help identify devices that may require less time to review compared with current practices. Criteria include the center's familiarity with a device and the device's hazard potential. The model replaces a risk-based approach that was shot down by FDA's medical device good manufacturing practice advisory committee in 1997 because it weighted medical device reporting data too heavily.

CDRH Office of Compliance deputy director Phil Frappaolo says that in addition to using this new model as a way to help decide how intensive a premarket review should be, the center could use it to identify devices that require closer postmarket surveillance and inspection.

Although the center does not yet have a formal process for routine device-hazard evaluations, the model will help officials establish what it is about a device that might or might not be hazardous, according to CDRH medical officer Barbara Silverman. Inspired by the European device classification system, the model uses a computer-driven questionnaire "attached with a decision logic" to assign devices into one of three categories according to their risk level.

According to Silverman, the questions first try to ascertain whether a device is proposed for a new use; hazards are then broken down by determining whether the device is an implant or sustains a critical body function. The model is currently being tested with seasoned reviewers before its future is decided by center officials.

As for postmarket activity, because the center today does not have enough resources to inspect even the most critical devices every two years, Frappaolo says it will concentrate for now on Class III and significant-risk devices. However, he says the center's quality system inspection technique (QSIT) has been shown to save time and will allow resources to be shifted to some Class II and Class I devices in the near future.

Postmarket surveillance studies should be considered in lieu of more-burdensome approaches to show effectiveness in device modifications, according to a "first-step" proposal offered to FDA by a HIMA-led task force in March. HIMA also suggested that the agency should rely on existing device-modification guidance for consultation in determining if prior review by FDA is required.

The task force was created in response to FDA's public request for suggestions on how CDRH can implement a provision of FDAMA that requires FDA to seek the "least-burdensome" means of establishing substantial equivalence or effectiveness in device submissions.

The proposal outlines a least-burdensome hierarchy table for FDA to consider when determining how much evidence a device manufacturer must submit for design changes. In the table, the least-burdensome level will require no prior FDA review. Instead, manufacturers of Class I and Class II devices would need to maintain documentation showing effectiveness in design history files. Design changes to PMA devices would need to be described in annual reports.

The next level would require laboratory bench testing or animal studies, according to the table. Manufacturers at this level would submit verification or simulated-use validation data in premarket notifications (510(k)s) or PMA supplements "when [the] statutory threshold for submission is reached" (e.g., new indication for use). Three higher levels are also outlined, with the most burdensome requiring well-controlled, prospective clinical trials.

The task force recommended that FDA reviewers should "identify the specific scientific question that must be resolved to establish substantial equivalence (Class I or Class II devices) or effectiveness (Class III) that cannot be answered at a lower level of burden." This same principle should be applied to the "de novo classification" of devices to encourage acceptance of 510(k) submissions instead of PMA applications.

The proposal included a list of general concepts FDA could apply in implementing a least-burdensome approach, such as "the appropriate application of risk versus benefit in determining approval criteria" and the acceptance of historical data. There is also a list of concepts that lead to a burden becoming "unwarranted," such as when FDA's reason for insisting on a submission is not clearly explained, or when ad hoc requirements exceed recommendations found in existing FDA guidance. The task force also provided examples from industry experience illustrating when least-burdensome approaches have and have not been followed.

Defying conventional wisdom, Minneapolis-based Endocardial Solutions Inc. says it has been persuaded by FDA to file its second EnSite 3000 arrhythmia-mapping device submission as a PMA application instead of the 510(k) it had already submitted. The company's first 510(k) for the EnSite 3000 system (for right-atrial use) was filed last September and is still pending. The second, for left-ventricular use, was filed last December.

The EnSite 3000 provides a three-dimensional graphic display of the heart's activity. Endocardial vice president for finance and CFO Leota Pearson said that under the new PMA, FDA will be looking for additional clinical trials but that the exact number has not yet been established. The company will also be submitting additional information requested on manufacturing issues.

Company president and CEO Jim Bullock expressed optimism that the 510(k) for right-atrial use will be approved in time for a U.S. launch in the second quarter of 1999. Since the first half of 1998, the EnSite 3000 system has been marketed in Europe for both right-atrial and left-ventricular applications.

The manufacturer of a "detoxifier" device told FDA's endrocrinologic and metabolic drugs advisory committee on March 26 that its product, the BioLogic-DT system, can "help physicians to leverage the potential of Rezulin with much greater safety." Rezulin is the major Parke-Davis drug for diabetes that has attracted increasing concern over its toxicity since it entered the United States market.

HemoTherapeutics Inc. executive vice president for clinical development Tom Halstead said the device "is designed to immediately and permanently clear drug metabolites and numerous liver toxins from a patient's system. With this technology, drug makers such as Parke-Davis will have the ability to support approved drugs and to continue the development of new drugs that would otherwise be limited or precluded from use because of related liver cytotoxicity." Halstead added that "of the over 3600 FDA-approved drugs, more than 1100 can potentially damage the liver. The buildup of liver enzymes can lead to ammonia toxicity, encephalopathy (confusion), coma, and even death. These adverse effects can be immediately and permanently reversed by HemoTherapeutic's technology."

The BioLogic-DT system, according to Halstead, functions like a "second liver" in clearing drug metabolites and numerous toxins, reducing or eliminating liver-damaging side effects. He described the product as a "compact, mobile, stand-alone, self-contained device that functions in maintaining appropriate blood chemistry concentrations through its ability to add specific electrolytes and glucose to the patient's blood. Unlike renal dialysis, the BioLogic-DT process is much gentler, the device is much simpler to operate, and lifelong treatments are unnecessary."

In a March 29 Federal Register notice, FDA said that it is exempting audiometers from the market prenotification requirements of the Federal Food, Drug, and Cosmetic Act, pursuant to a FDAMA provision giving it this discretion. The agency stated that it was acting on the basis of a petition from the Hearing Industries Association, and its subsequent determination that voluntary compliance with an American National Standards Institute consensus standard "obviates the need for premarket notifications."

Based on its own initiative and new information that provides adequate special controls for the devices, CDRH in a March 15 Federal Register notice proposed to reclassify 38 Class III (premarket approval required) devices to Class II (special controls). Comments are being received until June 14.

In an extensive listing of this new information, the agency's notice cites CDRH's biocompatibility guidance as a special control adequate to down-classify 27 devices, its sterility guidance for 23 devices, and numerous other guidances and documents for additional devices. Also cited are 37 private standards, and device-specific labeling for four devices (tinnitus masker, tympanostomy tube with semipermeable membrane, endometrial aspirator, and endoscopic electrocautery device and accessories). Design and performance testing is listed as a special control for four devices (external transcutaneous cardiac pacemaker [noninvasive], tympanostomy tube with semipermeable membrane, peritoneo-venous shunt, and endometrial aspirator).

The 38 devices proposed for reclassification include the following (in alphabetical order): airbrush IEC-601874.3400; annuloplasty ring; bipolar endoscopic coagulator; cardiopulmonary bypass arterial-line blood filter; cardiopulmonary bypass defoamer; cardiopulmonary bypass oxygenator; cardiovascular intravascular filter; cutaneous oxygen monitor; elbow-joint metal/polymer constrained cemented prosthesis; electrohydraulic lithotriptor; endometrial aspirator; endometrial brush; endometrial washer; endoscopic electrocautery and accessories; erythropoietin assay; esophageal prosthesis; external transcutaneous cardiac pacemaker (noninvasive); eye-valve implant; fibrin monomer paracoagulation test; high-permeability hemodialysis system; indwelling blood-hydrogen-ion concentration (pH) analyzer; indwelling blood-oxygen partial-pressure analyzer; keratoprosthesis; knee-joint patellofemoral polymer/metal semiconstrained cemented prosthesis; over-the-counter (OTC) denture cushion or pad; OTC denture reliner; OTC denture repair kit; pacemaker lead adapter; partially fabricated denture kit; peritoneo-venous shunt; rubella-virus serological agents; shoulder-joint metal/polymer semiconstrained cemented prosthesis; tinnitus masker; tracheal prosthesis; tympanostomy tube with semipermeable membrane; and vascular-graft prosthesis of less than 6-mm diam.

Becton Dickinson Corp. (Franklin Lakes, NJ) has requested an advisory opinion from FDA that its 510(k) clearance for its B-D At-Home Test for blood glucose monitoring preempts state laws that require clinical laboratories to accept specimens only on the order of a physician. The company maintains that the laws of several states have made it difficult to effectively market the product for over-the-counter use. Becton Dickinson says that the agency found that state laws were preempted by FDA's clearance of another at-home specimen collection kit, the Home Access HIV-1 Test system.

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